Abstract 321: Combination Dri With At1R Blockade Does Not Confer Additional Benefit to Improvement in Myocardial Tissue Hypertrophy and Fibrosis
Data support the notion that direct renin inhibition and angiotensin type 1 receptor (AT1R) blockade improve myocardial hypertrophy and fibrosis. Even with contemporary use of AT1R blockade and renin inhibition, the burden of heart failure remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT1R blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular (LV) hypertrophy and interstitial fibrosis to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat which manifests increased expression of murine renin which, in turn, results in increased tissue RAS activity, aldosterone secretion and elevated SBP. Ren2 rats were treated with renin inhibition (aliskiren), AT1R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased SBP, serum aldosterone levels, LV and cardiomyocyte hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in LV tissue NADPH oxidase subunit Nox2 and 3-nitrotyrosine (3-NT) content along with increases in mammalian target of rapamycin (mTOR) and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in SBP and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone. Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.
- © 2012 by American Heart Association, Inc.